dbSNP rs977225003: CHM:c.49+273G>T (chrX-86047211-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_001362517.1(CHM):c.-496G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000029 in 413,440 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000030 ( 0 hom. 3 hem. )

Consequence

CHM
NM_001362517.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.379

Variant links:

Genes affected

CHM (HGNC:1940): (CHM Rab escort protein) This gene encodes component A of the RAB geranylgeranyl transferase holoenzyme. In the dimeric holoenzyme, this subunit binds unprenylated Rab GTPases and then presents them to the catalytic Rab GGTase subunit for the geranylgeranyl transfer reaction. Rab GTPases need to be geranylgeranyled on either one or two cysteine residues in their C-terminus to localize to the correct intracellular membrane. Mutations in this gene are a cause of choroideremia; also known as tapetochoroidal dystrophy (TCD). This X-linked disease is characterized by progressive dystrophy of the choroid, retinal pigment epithelium and retina. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2016]

CHM links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS2

High Hemizygotes in GnomAdExome4 at 3 XLR,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHM	NM_000390.4 link	c.49+273G>T		intron_variant	Intron 1 of 14	ENST00000357749.7	NP_000381.1	P24386-1A8K545

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHM	ENST00000357749.7 link	c.49+273G>T	intron_variant	Intron 1 of 14	1	NM_000390.4	ENSP00000350386.2	P24386-1
CHM	ENST00000615443.1 link	c.49+273G>T	intron_variant	Intron 1 of 4	1		ENSP00000484306.1	P24386-2
CHM	ENST00000467744.2 link	n.59+36G>T	intron_variant	Intron 1 of 2	5
CHM	ENST00000483950.1 link	n.78+273G>T	intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.0000270

AC:

AN:

111303

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000298

AC:

AN:

302137

Hom.:

Cov.:

AF XY:

0.0000312

AC XY:

AN XY:

96157

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9289

American (AMR)

AF:

0.00

AC:

AN:

14588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9118

East Asian (EAS)

AF:

0.00

AC:

AN:

20806

South Asian (SAS)

AF:

0.00

AC:

AN:

26759

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1260

European-Non Finnish (NFE)

AF:

0.0000497

AC:

AN:

181155

Other (OTH)

AF:

0.00

AC:

AN:

18158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000270

AC:

AN:

111303

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33469

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30509

American (AMR)

AF:

0.00

AC:

AN:

10511

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3555

South Asian (SAS)

AF:

0.00

AC:

AN:

2634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000565

AC:

AN:

53080

Other (OTH)

AF:

0.00

AC:

AN:

1496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

0.38

PromoterAI

0.054

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.60

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.60

Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs977225003

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over